Nucleoside derivatives often are potent anti-viral (e.g., HIV, HCV, Herpes simplex, CMV) and anti-cancer chemotherapeutic agents. Unfortunately their utility is often limited by two factors. Firstly, poor pharmacokinetic properties frequently limit the absorption of the nucleoside from the gut and the intracellular concentration of the nucleoside derivatives and, secondly, suboptimal physical properties restrict formulation options which could be employed to enhance delivery of the active ingredient.
Prodrugs (P. Ettmayer et al., J. Med Chem. 2004 47(10):2393-2404; K. Beaumont et al., Curr. Drug Metab. 2003 4:461-485; H. Bundgaard, Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities in Design of Prodrugs, H. Bundgaard (ed) Elsevier Science Publishers, Amersterdam 1985; G. M. Pauletti et al. Adv. Drug Deliv. Rev. 1997 27:235-256; R. J. Jones and N. Bischofberger, Antiviral Res. 1995 27; 1-15 and C. R. Wagner et al., Med. Res. Rev. 2000 20:417-45) afford one technique to improve absorption of the drug. Typical examples of prodrugs include compounds that have chemically labile groups linked to a functional moiety of the active compound. Alkylation, acylation or other lipophilic modification of the hydroxy group(s) on the sugar moiety have been utilized in the design of pronucleotides. These pronucleotides can be hydrolyzed or dealkylated in vivo, either enzymatically or chemically mediated, to generate the active compound.
Unfortunately many otherwise useful prodrugs exhibit limited aqueous solubility which present a significant formulation challenge. Traditional solutions to poor aqueous solubility include micronization to lower particle size and, when feasible, conversion of a neutral compound into a more water soluble salt.
Solid dispersions afford one approach to formulation of compounds with poor aqueous solubility. The utility of solid dispersion systems for pharmaceutical formulation applications has been reviewed (W. L. Chiou and S. Riegelman, J. Pharm. Sci. 1971 60(9):1281-1302; C. Leuner and J. Dressman, Eur. J. Pharm. Biopharm. 2000 50:47-60; A. T. M. Serajuddin, J. Pharm. Sci. 1999 88(10):1058-1066, A. Forster et al. Pharm. Technol. Eur. 2002 14(10):27; J. Breitenbach Eur. J. Pharm. and Biopharm. 2002:54:107-117; J. Breitenbach and M. Mägerlein Drugs and the Pharmaceutical Sciences 2003 133:245-260 and K. A. Coppens et al., Pharm. Technol. 2006 30(1):62-70). Solid dispersion systems include eutectic mixtures, solid solutions and suspensions, glass suspensions and solutions, amorphous precipitates in crystalline carriers. Solid dispersions are a convenient and effective technique to formulate poorly soluble active ingredients. Disintegration and dispersal of the solid solution or suspensions affords fine colloidal particles of the active ingredient which aid absorption of the active ingredient (AI) in the gastrointestinal (GI) tract.
Solid dispersions can be prepared by hot melt extrusion of a molten mixture of AI and carrier or by rapid evaporation of a solvent from a solution of the AI and a carrier. Various solid carriers have been incorporated into solid dispersions including polyethylene glycol (PEG), polyethyleneoxide (PEO), polyvinylpyrrolidine (PVP), polyvinylalcohol (PVA), hydroxypropyl methyl cellulose (HMPC), hydroxypropyl cellulose (HPC), carboxymethylethylcellulose (CMEC), hydroxypropylmethyl cellulose phthalate (HPMCP), polyacrylates, polymethylacrylates, urea and sugars (e.g., mannitol) (Leuner, supra). While numerous options clearly exist, identifying a carrier molecule with optimal properties for an individual active ingredient remains a significant task.
Among the first and most intensively studied solid dispersion formulations is griseofulvin and PEG (W. L. Chiou and S. Riegelman, supra). PEGs are available over a very broad range of molecular weights and PEG's with molecular weights of approximately 2,000 to 6,000 have optimal physical properties for preparing solid dispersions with griseofulvin. Griseofulvin has limited aqueous solubility and is notoriously poorly absorbed by the oral route. Solid dispersions of griseofulvin and PEG are marketed as Gris-PEG®. PEGs are not good surfactants and the incorporation of emulsifiers, e.g., polysorbate 80, polyethylenedodecyl ether (Brij® 35) or sodium dodecyl sulfate, into the solid dispersion enhanced the dissolution process. An increase in release rate by formulation as a solid dispersion in PEG4000 has been observed for other drugs including oxazepam (J. M. Gines et al., Int. J. Pharm. 1996 143:247-253), piroxicam (M. Fernandez et al., Int. J. Pharm. 1993 98:29-35), zoldipem (G. Trapani et al., Int. J. Pharm. 1999 184:121-130), ketoprofen (M. V. Margarit and I. C. Rodriguez, Int. J. Pharm. 1994 108:101-107), oxepam (R. Jachowicz et al., Int. J. Pharm. 1993 99:321-325), nifedipine (H. Suzuki et al., Chem. Pharm. Bull. 1997 45:1688-1693), phenytoin (R. Jachowicz, Int. J. Pharm. 1987 35:7-12), fenofibrate (M. T. Sheu et al., Int. J. Pharm. 1994 103:137-146), prednisolone (R. Jachowicz, Int. J. Pharm. 1987 35:1-5) and glyburide (G. V. Betageri et al., Int. J. Pharm. 1995 126:155-160).
In WO 97/49384 published Dec. 31, 1997, J. McGinity and F. Zhang disclose pharmaceutical formulations comprising a hot-melt extrudable mixture of a therapeutic compound and a high molecular weight poly(ethylene oxide) (PEO) optionally containing polyethyleneglycol as a plasticizer. The PEO utilized in the invention had a molecular weight range from 1,000,000 to 10,000,000. This application was subsequently granted as U.S. Pat. No. 6,488,963.
In U.S. Publication No. 2004/0253314 published Dec. 16, 2004, H.-U. Petereit et al. disclosed melt extrusion formulations comprising an active pharmaceutical ingredient and a (meth)acrylate copolymer comprised of 40 to 75 weight % of radically copolymerized C1-4 alkyl esters of acrylic acid or of methacrylic acid.
In U.S. Publication No. 2005/0048112 published Mar. 3, 2005, J. Breitenbach et al. disclose solid pharmaceutical dosage forms comprising a solid dispersion of at least one HIV protease inhibitor, at least one pharmaceutically acceptable water soluble polymer and at least one pharmaceutically acceptable surfactant wherein the water soluble polymer has a Tg (glass transition temperature) of at least about 50° C.
In U.S. Publication No. 2005/0044529 published Apr. 21, 2005, J. Rosenberg et al. disclose solid pharmaceutical dosage forms comprising a solid dispersion of at least one HIV protease inhibitor, at least one pharmaceutically acceptable water soluble polymer and at least one pharmaceutically acceptable surfactant.